Pharmaceutical compositions for intranasal administration comprising choline salts of succinic acid

ABSTRACT

The present invention relates to pharmaceutical compositions for the intranasal administration comprising a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salts thereof. Preferably, the pharmaceutically acceptable salt is selected from the group consisting of choline salt, sodium salt, potassium salt, and thiamine salt. Further, the present invention relates to methods for intranasal delivering compound of formula (I) and pharmaceutically acceptable salts thereof. Further, the present invention relates to methods for treating a neurodegenerative disease with using compositions of the present invention.

FIELD OF THE INVENTION

The invention relates to the use of choline salts of succinic acid inpharmaceutical compositions for intranasal administration, particularlyin compositions with a neuroprotective activity.

BACKGROUND OF THE INVENTION

Choline salts of succinic acid are biologically active substances.

RU patent 2228147 discloses the use of dicholine salt of succinic acidfor the treatment dyslipidemia, hyperlipidemia, and insulin resistance.

RU patent 2281766 discloses the method for improving cognitive functionwith the use of dicholine salt of succinic acid.

RU patent 2281765 discloses the method for the treatment of cerebralischemia with the use of dicholine salt of succinic acid.

Monocholine salt of succinic acid is known from the prior art and isdisclosed, for example, by published U.S. Pat. No. 5,124,061 as acomponent of compositions for increasing the resistance of plants todamage by freezing conditions.

However, there are no data in the art on the use of monocholine ordicholine salts of succinic acid as components in pharmaceuticalcompositions suitable for intranasal administration.

Surprisingly, it is demonstrated in the present invention that cholinesalts of succinic acid manifest a pronounced effect on brain functionunder intranasal administration, and these effects are achieved withdoses tens and hundreds times less than required to achieve the same oreven less effect when these salts are administered intraperitoneally.Moreover, intranasal route of administration of a choline salt ofsuccinic acid provides desirable central effects and avoids undesirablesystemic effects such as undesirable insulin secretion in response toinjections of choline salts of succinic acids. Thus, because ofintranasal administration of choline salts of succinic acid is nowpossible (1) to decrease effective doses of these salts and neverthelessto achieve desired central therapeutic effects and (2) to avoidundesired systemic adverse effects typical for other routes of delivery.

It is an object of the present invention to provide a pharmaceuticalcomposition for the intranasal administration comprising atherapeutically effective amount of choline salts of succinic acid.

It is an object of the present invention to provide a method fortreating neurodegenerative diseases comprising intranasallyadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of choline salts of succinic acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition for theintranasal administration comprising a therapeutically effective amountof a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyand intranasally acceptable carrier.

The term <<pharmaceutically acceptable salt” refers to non-toxic baseaddition salts. The pharmaceutically acceptable salts of the inventionare prepared by a reaction of compound of formula (I) with apharmaceutically acceptable base by methods well-known from the art.Such bases include, but are not limited to, ammonia; sodium base;potassium base; choline base; thiamine base; organic amines like astriethylamine, ethanolamine, dimethylethanolamine, diethanolamine, andtriethanolamine; 2-ethyl-6-methyl-3-hydroxypiridine; and basic aminoacids like arginine, ornithine, and lysine. Preferably, thepharmaceutically acceptable salt of the invention is selected from thegroup consisting of choline salt (compound of formula II), sodium salt(compound of formula III), potassium salt (compound of formula IV), andthiamine salt (compound of formula V).

The present invention further provides a pharmaceutical composition forthe intranasal administration comprising a therapeutically effectiveamount of a compound of Formula (II)

and a pharmaceutically and intranasally acceptable carrier.

The present invention further provides a pharmaceutical composition forthe intranasal administration comprising a therapeutically effectiveamount of a compound of Formula (III)

and a pharmaceutically and intranasally acceptable carrier.

The present invention further provides a pharmaceutical composition forthe intranasal administration comprising a therapeutically effectiveamount of a compound of Formula (IV)

and a pharmaceutically and intranasally acceptable carrier.

The present invention further provides a pharmaceutical composition forthe intranasal administration comprising a therapeutically effectiveamount of a compound of Formula (V)

and a pharmaceutically and intranasally acceptable carrier.

The term “therapeutically effective amount” refers to a nontoxic butsufficient amount of an active agent to provide the desired therapeuticeffect. Preferably, the therapeutically effective amount of compounds offormula (I) through (V) is from 0.01 to 30 mg per a unit dosage form ofcompositions of the present invention. More preferably, from 5 to 15 mgper a unit dosage form.

The term “intranasal administration” refers to delivery of thecomposition to any portion of the nasal epithelium.

The term <<pharmaceutically and intranasally acceptable carrier” refersto a one or more compatible solid or liquid filler diluents orencapsulating substances which are suitable for administration to anyportion of the nasal epithelium of a mammal, preferably a human.Typically, the carrier may be a liquid, solution, suspension, gel,ointment, lotion, or combinations thereof. Preferably, the carrier is apharmaceutically acceptable aqueous carrier.

The compositions of the invention are prepared by methods well-knownfrom the art in accordance with accepted pharmaceutical procedures, forexample, as described in Remington's Pharmaceutical Sciences,seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company,Easton, Pa., Eighteenth edition (1990).

The compositions of the invention can be prepared in a variety of unitdosage forms. Such forms are include, but are not limited to, nasaldrop, nasal spray, nasal gel, nasal ointment, and nasal powder. Thecontent of compounds of formula (I) through (V) is in the range from 0.1to 99%, preferably 0.5 to 10% by the weight of the composition.

The present invention further provides a method for delivering acompound of Formula (I)

to a mammal in need thereof comprising intranasally administering apharmaceutical composition comprising a therapeutically effective amountof the compound of Formula (I) or a pharmaceutically acceptable saltthereof, and a pharmaceutically and intranasally acceptable carrier.Preferably, the pharmaceutically acceptable salt is selected from thegroup consisting of choline salt, sodium salt, potassium salt, andthiamine salt.

The present invention further provides a method of treating a diseaseselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, Huntington's disease, cerebral ischemia and neurological damagedue to stroke, diabetic polyneuropathy, and amyotrophic lateralsclerosis; the method comprising intranasally administering to a mammalin need thereof a pharmaceutical composition comprising atherapeutically effective amount of the compound of Formula (I)

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyand intranasally acceptable carrier. Preferably, the pharmaceuticallyacceptable salt is selected from the group consisting of choline salt,sodium salt, potassium salt, and thiamine salt.

As used herein, the term “treating a disease” means treating,controlling, preventing and/or reducing one or more clinical signs(i.e., symptoms) of the disease in a mammal in need thereof.

Preferably, the therapeutically effective amount in the method of thepresent invention is 0.01 to 5 mg per kilogram of body weight of themammal, to more preferably, 0.1 to 1 mg per kilogram.

Nonexclusive examples of mammals of the invention include humans andcompanion animals such as cats and dogs. Preferably, the mammal is ahuman.

The following examples are presented to demonstrate the invention. Theexamples are illustrative only and are not intended to limit the scopeof the invention in any way.

Example 1

This example demonstrates preparation of compounds of formula (I)through (V).

A compound of formula (I) is prepared by mixing 12.1 g choline base with11.8 g succinic acid at room temperature without of a solvent. Resultingmixture is dissolved in acetone at ambient temperature; and the solutionis filtered through a filter. Compound (I) is recovered as ionic liquidby evaporating of acetone from the solution. ¹H NMR in D₂O: 2.41 (9H,s), 3.19 (4H, s), 3.49 (2H, t), 4.10 (2H, t). Formula: C9H19NO5. Found:C 48.82%, H 8.69%, and N 6.30%. Calculated: C 48.86%, H 8.66%, and N6.33%.

A compound of formula (II) is prepared by mixing of 2.2 g of thecompound of formula (I) with 1.2 g of choline base at ambienttemperature without of a solvent. The mixture is dried under vacuum andre-crystallized from isopropanol-acetone. Compound (II) is recovered asa white powder. ¹H NMR in D₂O: 2.37 (18H, s), 3.14 (4H, s), 3.49 (4H,t), 4.05 (4H, t). Formula: C14H32N2O6. Found: C 51.79%, H 9.98%, and N8.60%. Calculated: C 51.83%, H 9.94%, and N 8.63%.

A compound of formula (III) is prepared by mixing of 2.2 g of thecompound of formula (I) with 0.04 g of sodium hydroxide at ambienttemperature without of a solvent. The mixture is dried under vacuum andre-crystallized from isopropanol-acetone. Compound (III) is recovered asa white powder. ¹H NMR in D₂O: 2.35 (9H, s), 3.15 (4H, s), 3.46 (2H, t),4.00 (2H, t). Formula: C9H18NO5Na. Found: C 44.40%, H 7.49%, and N5.72%. Calculated: C 44.44%, H 7.46%, and N 5.76%.

A compound of formula (IV) is prepared by mixing of 2.2 g of thecompound of formula (I) with 0.056 g of potassium hydroxide at ambienttemperature without of a solvent. The mixture is dried under vacuum andre-crystallized from isopropanol-acetone. Compound (IV) is recovered asa white powder. ¹H NMR in D₂O: 2.31 (9H, s), 3.10 (4H, s), 3.45 (2H, t),4.02 (2H, t). Formula: C9H18NO5K. Found: C 41.63%, H 7.02%, and N 5.34%.Calculated: C 41.68%, H 6.99%, and N 5.40%.

A compound of formula (V) is prepared by mixing of 2.2 g of the compoundof formula (I) with 2.82 g of thiamine base at ambient temperaturewithout of a solvent. The mixture is dried under vacuum andre-crystallized from isopropanol-acetone. Compound (V) is recovered as awhite powder. Formula: C21H35N5O6S. Found: C 51.90%, H 7.31%, and N14.39%. Calculated: C 51.94%, H 7.27%, and N 14.42%.

Example 2

This example demonstrates compositions for intranasal administrationcomprising compound of formula (I).

Ingredient Content Compound of formula (I) 50 mg/ml Disodium phosphateUSP/Ph Eur qs to pH 5.0 Water for injections USP/Ph Eur to 1.0 mlCompound of formula (I) is dissolved in water for injection to thedesired volume, 0.4M disodium phosphate is added to pH 5.0. In thismanner, solution with concentration of compound of formula (I) of 50mg/ml is prepared. The solution is filtered through a sterilizing gradefilter (0.2 μm), and filled into USP/Ph Eur Type 1 glass vials (nominalspray volume 100 μL) which are closed with chlorobutyl stoppers. Thevials are assembled into the commercially available unit dose nasalspray device. The assembled device may be used to deliver unit doses ofcompound of formula (I) of 5.0 mg in a single administration. The fillednasal spray device is packaged into a plastic tray and placed inside acarton to provide protection from the light.

Example 3

This example demonstrates compositions for intranasal administrationcomprising compound of formula (II).

Ingredient Content Compound of formula (II) 50 mg/ml Succinic acid qs topH 5.0 Water for injections USP/Ph Eur to 1.0 mlCompound of formula (II) is dissolved in water for injection to thedesired volume, 0.4M succinic acid is added to pH 5.0. In this manner,solution with concentration of compound of formula (II) of 50 mg/ml isprepared. The solution is sterilized and filled into glass vials asdescribed in Example 1. The vials are assembled into the commerciallyavailable unit dose nasal spray device. The assembled device may be usedto deliver unit doses of compound of formula (II) of 5.0 mg in a singleadministration. The filled nasal spray device is packaged into a plastictray and placed inside a carton to provide protection from the light.

Example 4

This example demonstrates compositions for intranasal administrationcomprising compound of formula (III).

Ingredient Content Compound of formula (III) 50 mg/ml Succinic acid qsto pH 5.0 Water for injections USP/Ph Eur to 1.0 mlCompound of formula (III) is dissolved in water for injection to thedesired volume, 0.4M succinic acid is added to pH 5.0. In this manner,solution with concentration of compound of formula (III) of 50 mg/ml isprepared. The solution is sterilized and filled into glass vials asdescribed in Example 1. The vials are assembled into the commerciallyavailable unit dose nasal spray device. The assembled device may be usedto deliver unit doses of compound of formula (III) of 5.0 mg in a singleadministration. The filled nasal spray device is packaged into a plastictray and placed inside a carton to provide protection from the light.

Example 5

This example demonstrates compositions for intranasal administrationcomprising compound of formula (IV).

Ingredient Content Compound of formula (IV) 50 mg/ml Succinic acid qs topH 5.0 Water for injections USP/Ph Eur to 1.0 mlCompound of formula (IV) is dissolved in water for injection to thedesired volume, 0.4M succinic acid is added to pH 5.0. In this manner,solution with concentration of compound of formula (IV) of 50 mg/ml isprepared. The solution is sterilized and filled into glass vials asdescribed in Example 1. The vials are assembled into the commerciallyavailable unit dose nasal spray device. The assembled device may be usedto deliver unit doses of compound of formula (IV) of 5.0 mg in a singleadministration. The filled nasal spray device is packaged into a plastictray and placed inside a carton to provide protection from the light.

Example 6

This example demonstrates compositions for intranasal administrationcomprising compound of formula (V).

Ingredient Content Compound of formula (V) 50 mg/ml Succinic acid qs topH 5.0 Water for injections USP/Ph Eur to 1.0 ml

sCompound of formula (V) is dissolved in water for injection to thedesired volume, 0.4M succinic acid is added to pH 5.0. In this manner,solution with concentration of compound of formula (V) of 50 mg/ml isprepared. The solution is sterilized and filled into glass vials asdescribed in Example 1. The vials are assembled into the commerciallyavailable unit dose nasal spray device. The assembled device may be usedto deliver unit doses of compound of formula (V) of 5.0 mg in a singleadministration. The filled nasal spray device is packaged into a plastictray and placed inside a carton to provide protection from the light.

Example 7

This example demonstrates methods for intranasal administration ofcompositions comprising compounds of formula (I) through (V).

The patient removes the packaging from the nasal spray device whichcontains a sterile solution of one of compounds of formula (I), (II),(III), (IV), or (V) and then inserts the nozzle of the device into anostril and articles is to administer a single dose.

Example 8

This example demonstrates methods for treating neurodegenerativedisorders in mammals in need thereof.

A disease relevant to human Alzheimer's disease was induced by injectionof beta-amyloid peptide 25-35 (beta-amyloid) into nucleus basalismagnocellularis (NBM) of rat brains as described by Harkany T et al. inBehav Brain Res. 1998 90(2):133-45. Beta-amyloid was administeredbilaterally into NBM of male Wistar rats in dose of 2 μg per each side.On day 16^(th) after the amyloid injection, rats received intranasallyor intraperitoneally compositions comprising a water solution of 1 mg/kgof compounds of formula (I), (II), (III), (IV), or (V) for 7 days singlya day. Control rats received saline intranasally. On day next to thelast day of the treatment, passive avoidance performance in rats wastested for two consecutive days. A two-compartment, step-through,passive avoidance apparatus consisting of illuminated (25×40×25 cm) anddark (25×40×25 cm) compartments attached to an electrified grid floorand separated by a guillotine door (8×8 cm) was used. In the acquisitiontrial, the rat was placed in the illuminated compartment in a positionits tail directed to the closed door for 2 min to habituate to theapparatus. The guillotine door was opened and time to enter to darkcompartment was recorded. When the rat entered to dark compartmentcompletely (four foots in dark compartment), the guillotine door wasclosed and the rat was delivered an electrical shock of 0.8 mA for 3 secthrough the grid floor. After the shock, the rat was immediately placedin home cage. In the retention trial, conducted 24 h after theacquisition trial, the rat was placed in the illuminated compartment andthe retention latency to enter into the dark compartment was recordeduntil 180 s had elapsed. The latency was accepted for 180 s, if the ratdid not enter the dark compartment for 180 s. Data are presented asretention latency mean±SD (n=8).

Groups Latency, s Control 48 ± 11 Compound of formula (I), intranasally103 ± 18* Compound of formula (I), 55 ± 18 intraperitoneally Compound offormula (II), intranasally  98 ± 21* Compound of formula (II), 45 ± 16intraperitoneally Compound of formula (III),  87 ± 19* intranasallyCompound of formula (III), 53 ± 28 intraperitoneally Compound of formula(IV),  65 ± 16* intranasally Compound of formula (IV), 49 ± 17intraperitoneally Compound of formula (V), intranasally  92 ± 17*Compound of formula (V), 59 ± 23 intraperitoneally *Differssignificantly of control (P < 0.05).

Thus, intranasal administration of composition comprising compounds offormula (I) through (V) is much more effective than intraperitonealadministration. Intranasally treated rats demonstrate significantimprovement in learning and memory as compared to control rats, whereasintraperitoneally treated rats do not.

1. A pharmaceutical composition for the intranasal administrationcomprising a therapeutically effective amount of a compound of Formula(I)

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyand intranasally acceptable carrier.
 2. The composition of claim 1,wherein the pharmaceutically acceptable salt is a compound of Formula(II).

3-5. (canceled)
 6. A method for delivering a compound of Formula (I)

to a mammal in need thereof comprising intranasally administering apharmaceutical composition comprising a therapeutically effective amountof the compound of Formula (I) or a pharmaceutically acceptable saltthereof, and a pharmaceutically and intranasally acceptable carrier. 7.The method of claim 6, wherein the pharmaceutically acceptable salt isselected from the group consisting of choline salt, sodium salt,potassium salt, and thiamine salt.
 8. A method of treating a diseaseselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, Huntington's disease, cerebral ischemia and neurological damagedue to stroke, diabetic polyneuropathy, and amyotrophic lateralsclerosis; the method comprising intranasally administering to a mammalin need thereof a pharmaceutical composition comprising atherapeutically effective amount of the compound of Formula (I)

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyand intranasally acceptable carrier.
 9. The method of claim 8, whereinthe pharmaceutically acceptable salt is selected from the groupconsisting of choline salt, sodium salt, potassium salt, and thiaminesalt.